Cytokines reinstate NK cell-mediated cancer immunosurveillance

Abstract

In healthy individuals, cells that lose expression of MHC class I molecules are quickly targeted for elimination by NK lymphocytes. A paradox in cancer immunology is the observation that many tumor cells often have a drastic reduction of MHC class I molecules, yet these cells are not eliminated by NK cells, as they should be. In this issue of the JCI, Ardolino et al. demonstrate that NK cells that infiltrate MHC class I-deficient tumors acquire an anergic state that can be reversed by particular combinations of exogenous cytokines. These results indicate that IL-12 plus IL-18 or a recombinant interleukin engineered to stimulate the IL-2 receptor β/γ heterodimer (but not the IL-2 receptor α/β/γ complex) have the potential to be used clinically to reinstate immunosurveillance against MHC class I-deficient tumors.

Figure 1. Restoring intratumoral NK cell functions with cytokines.

When tumor cells lose MHC class I expression, which can occur for a variety of reasons, they disarm the function of NK cells, which become “unlicensed.” However, upon administration of the combination of IL-12 plus IL-18 or H9, NK cells regain their functions, including phosphorylation of the stress kinase ERK1/2, production of granzyme B, and secretion of IFN-γ, and recover their capacity to control tumor progression.